A special class of molecules that could have bearing on various neurological disorders, as well as potential treatments for them, is the subject of a new study. Scientists from the Florida campus of The Scripps Research Institute (TSRI) received a $1.4 million, three-year grant from the National Institute of Mental Health of the National Institutes of Health (NIH) to explore the development of drug candidates for a wide range of conditions, including circadian rhythm disorders. Principal investigators will be Patrick R. Griffin, chair of the Department of Molecular Therapeutics at Scripps Florida, and Theodore Kamenecka, a TSRI associate professor, according to a story in Drug Discovery & Development (http://www.dddmag.com/news/2015/07/scientists-receive-14m-study-drug-candidates-neurological-disorders-other-diseases?et_cid=4704246&et_rid=45505806&location=top).
Grant 1R01MH108173 will analyze RORs (retinoic acid receptor-related orphan receptors), a class of molecules said to play a role in the expression of genes involved in carbohydrate and fat metabolism, inflammation and circadian rhythm. Disruptions in circadian rhythm, the pattern of activity and rest over a 24-hour daily cycle, have been linked to depression, bipolar disease and schizophrenia.
According to Prof. Griffin, "While the functions of other ROR receptors have been widely studied, little is known about RORbeta. The new grant will allow us to expand and improve our experimental compounds to study RORbeta function in depth. This line of research should increase our understanding of this receptor as well as circadian rhythm and related disorders."
Although the research is not specifically targeted at developing drug candidates, it will include studies of the new optimized compounds in experimental models of a range of diseases. Follow-on grants could lead to drug development.
According to an article by AM Jetten National Center for Biotechnology Information, U.S. National Library of Medicine (Retinoid-related orphan receptors -- RORs: critical roles in development, immunity, circadian rhythm, and cellular metabolism), "The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORalpha, -beta, and -gamma (NR1F1-3), their mechanism of action, physiological functions and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORalpha plays a critical role in the development of the cerebellum, that both RORalpha and RORbeta are required for the maturation of photoreceptors in the retina, and that RORgamma is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes" (http://www.ncbi.nlm.nih.gov/pubmed/19381306).
